rs776075679
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_004820.5(CYP7B1):c.1460_1461insT(p.Leu487PhefsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L487L) has been classified as Likely benign.
Frequency
Consequence
NM_004820.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP7B1 | NM_004820.5 | c.1460_1461insT | p.Leu487PhefsTer11 | frameshift_variant | 6/6 | ENST00000310193.4 | |
CYP7B1 | XM_017014002.2 | c.1526_1527insT | p.Leu509PhefsTer11 | frameshift_variant | 7/7 | ||
CYP7B1 | NM_001324112.2 | c.1234-6859_1234-6858insT | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP7B1 | ENST00000310193.4 | c.1460_1461insT | p.Leu487PhefsTer11 | frameshift_variant | 6/6 | 1 | NM_004820.5 | P1 | |
CYP7B1 | ENST00000523954.1 | n.508-6859_508-6858insT | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250568Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135506
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461238Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726906
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Leu487Phefs*11) in the CYP7B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the CYP7B1 protein. This variant is present in population databases (rs776075679, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 23812641, 26374131). ClinVar contains an entry for this variant (Variation ID: 498356). This variant disrupts a region of the CYP7B1 protein in which other variant(s) (p.Gly490Cys) have been observed in individuals with CYP7B1-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at